The present disclosure relates to a composition for prophylaxis or treatment of vascular or valvular calcification including a dipeptidyl peptidase-4 (DPP-4) inhibitor.
Cardiovascular calcification contributes to exacerbation of hypertension, heart failure, acute coronary syndrome, and valvular diseases, and thus causes various complications. Also, a variety of epidemiological studies have found that vascular calcification independently increases the mortalities. Vascular calcification occurs in a mechanism similar to an osteogenic program after a normal prenatal stage or a bone fracture, and is activated in diseases such as old age, diabetes, chronic renal failure, chronic inflammatory diseases. The loss of minerals in bones is accelerated by an inflammatory response, and the free minerals are endocytosed into abnormal vascular endothelial cells.
Vascular endothelial dysfunction is an important mechanism for vascular calcification. Normally, endothelial nitric oxide synthase (eNOS) is constitutionally expressed at a certain level in vascular endothelial cells, endomyocardial cells, atrial cells, vascular smooth muscle cells, respiratory endothelial cells, and the like, and serves to adjust a vascular tone and maintain homeostasis of vascular endothelial cells by forming nitric oxide (NO). When the dysfunction of eNOS appears, isoenzymes, such as neuronal NOS (nNOS) or inducible NOS (iNOS), which have structures and functions similar to the eNOS, increase compensatorily to replace the role of eNOS, but do not continuously maintain normal vascular endothelial cell functions with ease. Therefore, pathologic alterations in blood vessels including atherosclerosis occur at an early stage. In a laboratory animal model studying an effect of endothelial nitric oxide synthase (eNOS) on the cardiovascular system, that is, an endothelial nitric oxide synthase knockout (eNOS KO) animal model, it was known that the onset of hypertension and atherosclerosis increases, and wide lesional areas and severe remodeling occur after apoplexy and myocardial infarction, compared to the control.
The present inventors have made an ardent effort to elucidate a cardiovascular calcification procedure and develop a therapeutic drug for cardiovascular calcification, and found that DPP-4 is expressed at an increased level in an animal model in which the cardiovascular calcification is induced, and an inhibitor of DPP-4 effectively inhibits calcification of blood vessels and valves. Therefore, the present disclosure has been completed based on these facts.